Methyl-chlorpropyl formamide



l atented Aug. 11, 1953 METHYL-CHLORPROPYL FORMAMIDE Meyer Sletzinger,Forest Hills, N. Y., and Max Tishler, W'estfield, N. J., assignors toMerck & 00., Inc., Rahway, N. J., a corporation of New Jersey NoDrawing. Original application July 2, 1948, Serial No. 36,803. Dividedand this application January 31, 1951, Serial No. 208,841

1 Claim. (Cl. 260-561) 1 2 This invention relates to the manufacture ofaration procedure which results in a considercompounds possessinanalgesic and anesthetic able loss of the desired isomer. action. Inparticular, it is concerned with an It is now discovered that thedesired 2,2-diimproved synthetic method for preparing 2,2- phenyl 3methyl 4 dimethylamino budiphenyl 3 methyl 4 dimethylamino butyronitrilecan be prepared by a novel process tyronitrile and with novel chemicalcompounds which does not produce any of the unwanted isouseful asintermediates in the preparation of this meric nitrile. This improvedmethod thus elimcompound. 2,2 diphenyl 3 methyl 4 diinates the loss dueto formation of the by-prodmethylamino-butyronitrile is itself animportant uct isomer and at the same time avoids the need intermediatein the synthesis of isoamidone, 1- for a complicated separationprocedure with its dimethylamino 2 methyl 3,3 diphenylattendant lossesof the desired isomer. This hexanonel and salts thereof. Isoamidone andnovel process is conducted as follows: l-rnethits salts possessanalgesic action and may be y1a 0 -p 0l (compound 1 w) is used assubstitutes for morphine. acted with formamide to produce l-methyliorm-This application is a division of application amido-a-propa ol p d 2)which is treat- Serial No. 36,803, filed July 2, 1948, now U. S. ed withthionyl chloride to form l-methylform- Patent 2,574,595, and relates, inparticular, to amido-2-chloropropane (compound 3). This the preparationof 1-methylformamido-2-chlorocompound is then treated with the reactionprodpropane, which is utilized as an intermediate in not ofdiphenylacetonitrile and sodamide to proour improved method for thesynthesis of 2,2- duce 2,2 diphenyl 3 methyl 4 methyldiphenyl 3 methyl 4dimethylamino buformamido-butyronitrile (compound i) which istyronitrile. reduced by treatment with formic acid and tri- 2,2 diphenyl3 methyl 4 dimethylaminooxane (or paraformaldehyde) to form thedebutyronitrile has been prepared previously by sired 2,2 p yl 3 methyl4 e y reacting 1-dimethylamino-2-chloropropane with amino-butyronitrile(compound 5). These reacdiphenylacetonitrile as described by Schultz eta1. tions may be chemically represented as follows:

HCONH: S0011 CHaCHOHCH NHCHt CHaCHOHCHzNCHa CHsCH-CHgNCHI H O l H Ol(CuH5)2CHCN NaNHz Reduction (CdIshC-GH-CHgNCH: (C6H5)2?CHCHINCHI N H:H: ON OH; HO

(J. A. C. S. 69, 188-189, January 1947). As The reaction between the1-methylamino-2- pointed out by these workers, however, when propanoland the formamide is carried out by 2,2 diphenyl 3 methyl 4dimethylaminoheating the reactants together at a temperaturebutyronitrile is prepared by this procedure, there 0f about The reactionis preferably is obtained, at the same time and mixed with thisconducted under reflux, at a temperature of compound, the isomericit-rile 2,2 dipheny1 4 150- -160 C. At thistemperature the reaction ismethyl e climethylamino butyronitrile. The (manly In about 3 hours- Thelatter nitrile isomer constitutes an unwanted byporno? 0f formarinde canbe vamfd over q duct since it cannot be converted to isorange for exampamounts Varymg from equl' molecular proportions up to 4 moles offormamldoneamide per mole of l-methylamino-i2-propanol Mor v thepreparatlol} of f can be employed without affecting the yield or rectlyfrom the mixture of isomeric nltriles has quality of the product.Instead of employing an not proven feasible- In Order to Prepare excessof formamide, it is possible to use an examidone, it has thereforepreviously been necescess of l..methylamino g-propanol, if desired Sa yisolate the d d D y When an excess of formamide is used, theexyl-4-dimethylamino-butyronitrile from the mixcess formamide isconveniently separated from ture and this has necessitated a complicatedsep- 55 the reaction mixture by fractional distillation;

the residual 1 methylformamido 2 propanol product (compound 2) bepurified by fractional distillation, if desired. It ordinarilypreferred, however, to employ ecuiimolecular quanti ties of1-rnethylamino-2-propanol and formamide since this procedure itunnecessary to separate excess formamide from the l-methylformamido-2-propanol product; and the material, as produced can beused directly in the following process operation.

The 1methylformamidoe2-propanol, either in pure form or as the crudereaction mixture resulting from the previous procedure described in thepreceding paragraph is then reacted with thionyl chloride to produce thedesired l-methylforrnamido-2-chloropropane. The reaction with thionylchloride is ordinarily carried out in the presence of a tertiary amine,such as dimethylaniline, or preferably a tertiary heterocyclic aminesuch as pyridine. If desired, the reaction can be run in solution in ahydrocarbon solvent such as benzene or toluene, or in a hydrocarbonsolvent containing said tertiary amine.

The reaction is conducted by adding thionyl chloride dropwise to thesolution of the l-rnethylformamido-Z-propanol in the tertiary amineand/or the hydrocarbon solvent. The rate of addition of the thionylchloride is adjusted so as to avoid too rapid a reaction and possibleoverheating of the reaction mixture. The temperature at which thethionyl chloride should be added can vary between wide limits, about 045(3., without any variation in the yield of product. After the additionof the thionyl chloride is complete, the mixture is heated attemperature of about 70-10%? C. until no more fumes of sulfur dioxidecan be detected. The reaction time varies depending on the temperature,but ordinarily the reaction is complete in about 7 to 10 hours.

Ihe reaction mixture is allowed to cool to room temperature and thel-methylformarnido-Z- chloropropane recovered therefrom by conven tionalmeans. For example, the reaction mixture is shaken with an organicsolvent, such as chloroform, benzene, toluene, and the like, and asaturated aqueous solution of an inorganic salt such as sodium chloride,potassium chloride, sodium sulfate, and the like. The non-aqueous layeris then washed with a weakly alkaline aqueous solution such as aqueoussodium bicarbonate solution, aqueous potassium carbonate solution,aqueous sodium carbonate solution, and the like, until neutral. Thenon-aqueous layer is washed with water, dried and distilled to producethe 1- methylformami'do 2 chloropropane product (compound 3) Thiscompound is treated with the reaction product of diphenylacetonitrileand sodamide. The diphenylacetonitriie is mixed with an equivalent molarquantity of scdamide and an inert solvent such as xylene, toluene orliquid petroleum having a boiling point at least about 110 C. Theresulting mixture is heated and stirred until the quantitative amount ofammonia has been liberated. The reaction is ordinarily carried out at atemperattue of about l05-l10 C. under reflux and in the presence of anitrogen atmosphere.

This reaction mixture is then cooled to about 36 C. and thel-methylformamido-2-chloropropane is added thereto, preferably dropwise,with stirring. Prior to the addition of thel-methylformamido-Z-chloropropane, it is ordinarily preferred to add asmall amount of an ionic iodide, as for example sodium iodide, althoughthe reaction can be carried out, if desired, in the absence of theiodide compound. During the addition of the l methylformamido 2chloropropane the temperature of the reaction mixture rises of its ownaccord to 35 0., or higher. The resulting mixture is then heated slowlyto about -115 C. and maintained at this temperature until the reactionis substantially complete. This ordinarily requires about 3 hours. Thereaction mixture is then treated with a mixture of water and awater-immiscible solvent. Among the Water= immiscible solvents which maybe employed are hydrocarbon solvents, such as benzene, or chlorinatedhydrocarbon solvents such as chloroform. The layers are separated, theaqueous layer extracted with additional solvent and the nonaqueousextracts are combined, clarified by filtration and evaporated to drynessto produce crude 2,2 diphenyl 3 methyl 4 methyliorinamido-butyronitrile.This product is conveniently purified by recrystallization from otherwhereby it is obtained in substantially pure form in a singlerecrystallization operation. Ether is the preferred solvent forrecrystallization of the product since it is selective for theimpurities, w are thus left the mother liquor. Other so nts may beemployed if desired, but when using solvents other than ether, it isbest to first still the rection mixture to remove diphenylacetonitrileand other impurities; the residual material is then taken up in thesolvent and crystallized.

.s pointed out above, the nitrile product prein this consists only ofthe desired 2,2- diphenyl 3 methyl methylformamidobutzuonisrileuncontaminated with any isomeric product. This is clearly important inview of the fact that when diphenylacetonitrile is reacted with 1dimethylainino 2 chloropropane, the product contains both2,2-diphenyl-3-methyl-4- dimethylao-butyronitrile and 2,2-dip-henyl-4-nethylamino-butyronitrile.

It is a further advantage of the present invention that this2,2diphenyl-3-nethyl l-methylamidc-butyronitrile can be reduced to thecorrespon 1g i-dime-thyl mine-compound withaffecting the nitrilelinkage, which is known to be sensitive reducing agents. This isaccomplished by reacting said 2,2-diphenyl-3- methyl l methylformamidobutyronitrile with formic acid and trioxane. Instead of triox ane,paraformaldehyde may be used although the yields, when paraformaldehydeis used, are somewhat lower.

The mixture of reactants is heated under reflux until the reaction issubstantially complete. The end of the reaction is convenientlyascertained by adding a drop of the reaction mixture to an excess ofwater; when a clear solution results it is an indication that thereaction is complete. The reaction is ordinarily carried out at atemperature of about '.-l60 C. The time necessary for complete reactionvaries, but at the above temperature, the reaction is usually completein about 5 days.

The reaction mixture is cooled to 25 6., diluted with water and madealkaline with a strong inorganic base, such as aqueous sodium hydroxide,aqueous ammonium hydroxide, and the like. A white semi-solid materialseparates which, on standing, crystallizes completely. This material isrecovered by filtration, washed with water and dried to produce 2,2-diphenyl 3-methyl-4-dimethylamino-butyronitrile. Since this material isobtained by reduction of the single isomer 2,2-

Example 1 89 gms. (1 mole) of 1-methylamino-2-propanol were mixed with180 gms. (4 moles) of formamide, and the resulting solution was heatedto 150-160 C. with stirring and under reflux for about 3 hours. At theend of this time, the reaction mixture was an orange color. The reactionmixture was cooled and fractionally distilled using a Vigreux column.The first fraction was boiled at 63-71 C./1 mm. and weighed 136.0 gms.;15 214490. This product was practically pure formamide. The secondfraction boiled at 71-92 C./0.5 mm. and weighed 14.9 g.; n :1.4645. Thethird fraction boiled at 92 C./0.5 mm. and weighed 94.5 gms; 7ZD23:1.4665. The total weight of the last fractions was 109.4 gms. andrepresented a yield of 93% of 1-methylformamido-2-pr0panol based on 1-methylamino 2 propanol starting material. Anal. Calcd for C5I-Ii1O2N1 C,51.28; H, 9.40; N, 11.96. Found: C, 51.18; H, 9.64; N, 11.91.

Example 2 A mixture of 228 gms. (2 moles) ofl-methylformamido-Z-propanol and 158 gms. (2 moles) of pyridine (driedover KOH) was stirred and cooled to C., and 250 gms. (2.1 moles) ofthionyl chloride was then added dropwise over a period of 2 hours,during which time the temperature was maintained at 0-10 C. The massbecame very thick at the end of the addition, rendering the stirringdifficult. After the thionyl chloride had been added the mixture waskept at 0-10 C. for an additional hour. The cooling was thendiscontinued and the reaction temperature allowed to rise of itself. Thetemperature reached a maximum of 75 C. The mixture was then heated to90-100 C. for 7 hours at which time no more fumes of sulfur dioxidecould be detected. The reaction mixture was cooled to 30 C., dissolvedin 650 cc. of chloroform and washed with three 150 cc. portions ofsaturated sodium chloride solution. The combined aqueous extracts werewashed with 150 cc. of chloroform. The combined organic layers were thenwashed with 200 cc. of a saturated solution of sodium bicarbonate andthen solid sodium bicarbonate was slowly added With stirring until thesolution was neutral. The chloroform solution was dried over anhydrousmagnesium sulfate, filtered and the chloroform evaporated from thesolution to dryness in vacuo. The residual oil was fractionallydistilled to produce 171.8 gms. of 1 methylformamido 2-chloropropane; B.P. 78 C./2.5 mm.; 'n :1.4689; yield approximately 63.3% of theory. Thismaterial gave a negative test for ionic halogen when treated in aqueoussolution with silver nitrate. Analysis, Calcd for C5I-I1oC1NOZ C, 44.28;H, 7.40; N, 10.33; 01, 26.15. Found: C, 44.49; H, 7.70; N, 10:28; Cl,25.88.

Example 3 A mixture of 64 gms. (0.72 mole) of l-methylamino-Z-propanoland 33.3 gms. (0.74 mole) of formamide was heated at 150-160 C. withstirring for about 3 hours during which time about 98% of thetheoretical amount of ammonia was evolved. The reaction mixture was thencooled to room temperature, and an aliquot of the reaction solution wasanalyzed by fractional distillation which showed a 92% yield ofl-methylformamido-Z-propanol based on l-methylamino- 2-propanol startingmaterial; B. P. 103l24 C./4 mm.; n :1.4652.

Example 4 32 gms. (0.359 mole) of crude l-methylformamido-2-propanolprepared as described in Example 3 above, was dissolved in 128 cc. ofchloroform and 28.2 gms. (0.357 mole) of pyridine. 44.8 gms. (0.377mole) of thionyl chloride were added to the above solution over a periodof 30 minutes during which time the temperature rose to 60 C. Themixture was then heated under reflux at 73 C. for about 10 hours. Thereaction solution was allowed to cool to room temperature and thesolution was washed with three 25 cc. portions of saturated sodiumchloride solution. The combined aqueous extracts were washed with 25 cc.of chloroform. The combined organic layers were washed with 35 cc. ofsaturated sodium bicarbonate solution until neutral and then washed with40 cc. of water. The chloroform layer was dried over 10 gms. ofanhydrous sodium sulfate, filtered, and the sodium sulfate washed with10 cc. of chloroform. The combined filtrate and washes were fractionallydistilled in vacuo to produce 40.3 gms. of 1-methylformamido-2-chloropropane; B. P. 139- 141 C./58 mm. n :1.4693;yield 83% of theory based on the 1-methylformamido-2-propanol startingmaterial. The product showed, upon titrating, 98.5% organic halide withonly a trace (0.0004 eq./gm.) ionic halide.

Example 5 A solution of 19.3 gms. (0.10 mole) of diphenylacetonitrile in40 cc. of anhydrous xylene was mixed with a slurry of 3.9 gms. (0.10mole) of sodamide in 35 cc. of xylene. The resulting mixture was heatedand stirred at a temperature of 105-110 C. under reflux and under anitrogen atmosphere. After 2 hours at this temperature the solid turneda tan color and the quantitative amount of ammonia had been liberated.At this point the temperature was lowered to 30 C. and 0.27 gm. ofsodium iodide was added followed by the dropwise addition, over a periodof 15 minutes, of 6.8 gms. (0.05 mole) ofl-methylformamido-Z-chloropropane. During the addition, the temperaturerose to about 35 C. of its own accord. The temperature of the reactionmixture was then raised over a period of 20 minutes to -115" C. and thereaction mixture Was maintained at this temperature for 3 hours.

The mixture was then cooled to room temperature and extracted with two45 cc. portions of water. The aqueous extracts were washed with 50 cc.of benzene and the organic extracts were combined, filtered from a smallamount of insoluble material and evaporated to dryness in vacuo on asteam bath. The residual material weighing 23.2. gms. was dissolved in100 cc. of ether and the solution cooled overnight at 510 C. Thecrystalline precipitate which separated was recovered by filtration anddried to produce 8.4 gms. of2,2-diphenyl-3-methyl-4-methylformamido-butyronitrile; M. P. 1275-1290.; yield 57.5% of theory. A sample of this material was furtherpurified by recrystallization from butanol. Analysis, Calcd forC19H20ON22 7 C, 78.08; H, 6.84; N, 9.63. Found: C, 78.31; H. 7.06; N,9.68.

The mother liquors from the filtration were evaporated to dryness andthe resulting residual material was then fractionally distilled at apressure of 1 mm. About 9.8 gms. of crude diphenyl-acetonitriledistilled at 130140 C./1 mm. The distillation was stopped when no moredistilled at this temperature and the residual material, which weighed2.7 gms., was dissolved in 20 cc. of ether and the solution cooledovernight at 5-10 C. The crystalline product which separated wasrecovered by filtration and dried to produce an additional 1.0 gm. of2,2-diphenyl-3- methyl-4-methylformamido-butyronitrile; M. P. 126-428C.; total yield was equal to 9.4 gms. which corresponds to 64.3% oftheory.

The unreacted diphenylacetonitrile resulting from the foregoingdistillation was recovered by slurrying the crude material (9.8 g. M. P.64-71.5 C.) with 2 cc. of isopropanol and the mixture heated to solutionon a steam bath. On cooling this solution, crystals separated which werefiltered and washed with 2 cc. of isopropanol and 2 cc. of petroleumether. The product was dried to produce 7.65 gms. ofdiphenylacetonitrile; M. P. 71.5-74 C.; this represents a recovery of58% of the unreacted diphenylacetonitrile.

Example 6 2 gms. of trioxane, 6 gms. Bil-100% formic acid and 5.84 gins.(0.02 mole) of 2,2-diphenyl-3- methyl 4 methylformamido-butyronitrilewere heated under reflux (temperature of the mixture 7-100 C.) for 112hours. At the end of this time a drop of the reaction mixture, whenadded to an excess of water, gave a clear solution indicating completereaction. The reaction mixture was cooled to 25 C. and poured into 100cc. of

water. The aqueous solution was then made basic with aqueous ammoniumhydroxide whereupon a white semi-solid material separated which, onstanding overnight, crystallized completely. The crystalline precipitatewas filtered and washed with water and dried to produce 5.1 gms. of2,2-diphenyl-3methyl-4-dimethylaminobutyronitrile; M. P. 63-64.5 C.;yield 91% of theory. The nitrile can be further purified, if desired, byrecrystallization from isopropanolpetroleum ether. The nitrile afterrecrystallization melts at about 67 C.

This material was further identified as follows: (a) Mixed M. P. withknown sample of 2,2 diphenyl 3 methyl-4-dimethylamino-butyronitrile ofM. P. 64-65" C. melted at 63-65 C.; (b) The picrate showed a M. P. of210-211 C. The mixed melting point of this picrate with known picrateshowed no depression of melting point; (e) The infra-red absorptionspectrum substantiated the structure.

Various changes and modifications may be made in our invention withoutdeparting from the spirit and scope thereof. Insofar as these changesand modifications are within the purview of the annexed claim, they areto be considered as part of our invention.

We claim:

l-Methylformamido-2-chloropropane.

MEYER SLETZINGER. MAX TISHLER.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,204,371 Loder June 11, 1940 2,232,598 Farlow Feb. 18, 19412,357,283 Peters Sent. 5. 1944

1. METHYLFORMAMIDO-2-CHLOROPROPANE.